The Journal of Antibiotics a Possible Role by of Bleomycin in Double-strand of Dna Bithiazoles Causing Scission

There are several lines of evidence indicating that the DNA-cleaving activity of bleomycin determines its cytotoxicity. (1) Most bleomycin analogs and derivatives which degrade isolated DNA are also active against living cells and vice versal) ; (2) some bacterial mutants selected for sensitivity to bleomycin lacked DNA-repair systems',') ; and (3) more degradation of DNA was observed in cells of a bleomycin-sensitive strain of a tumor than a resistant strain4). A characteristic of the degradation of DNA by bleomycin is the formation of double-strand breaks (dsb) independent of coincident single-strand breaks (ssb) in the complementary strand at near positions'). When covalently closed circular DNA (cccDNA or form I DNA) was used as substrate, the extent of production of ssb and dsb could be determined from the appearance of nicked, circular form II DNA and broken, linear form III DNA, respectively, under conditions where the dsb produced from random ssb would be negligible after low bleomycin exposures'). We used this system to evaluate the role of the bithiazole group of bleomycin by comparing the activity of the antibiotic with that of phleomycin, which has a thiazoline group and is otherwise identical to bleomycin. Some interaction of the bithiazole group with DNA, especially with guanine residues, has been proposed based on a fluorescence-quenching study6). The bithiazole group, with its coplanar structure, has also been proposed to intercalate into DNA7). The structural modification in phleomycin should cause a significant effect on the conformation of the molecule; phleomycin does not intercalate into DNA at alley.